Chemistry:Doxylamine

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Short description: First-generation antihistamine used as a short-term sedative and hypnotic (sleep aid)
Doxylamine
Skeletal formula of the doxylamine molecule
Ball-and-stick model of the doxylamine molecule
Clinical data
Trade namesUnisom, Vicks Formula 44 (in combination with Dextromethorphan), others
AHFS/Drugs.comMonograph
MedlinePlusa682537
Pregnancy
category
  • AU: A
  • US: B (No risk in non-human studies)
  • A (Briggs)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S3 (Pharmacist only)
  • US: OTC
Pharmacokinetic data
BioavailabilityOral: 24.7%[1]
Intranasal: 70.8%[1]
MetabolismHepatic (CYP2D6, CYP1A2, CYP2C9)[2]
Elimination half-life10–12 hours (range 7–15 hours)[2][3][4]
ExcretionUrine (60%), feces (40%)[5]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H22N2O
Molar mass270.376 g·mol−1
3D model (JSmol)
  (verify)

Doxylamine, sold under the brand name Unisom among others, is an antihistamine medication which is used in the treatment of insomnia and allergies. It is also used to treat morning sickness in pregnant women in combination with pyridoxine (vitamin B6). Doxylamine is available over-the-counter, and is used in nighttime cold medicines, such as NyQuil, as well as in pain medications containing acetaminophen and codeine, to help with sleep. The medication is taken by mouth.

Side effects of doxylamine include dizziness, drowsiness, grogginess, and dry mouth, among others.[6][4] Doxylamine is an antihistamine—specifically an inverse agonist of the histamine H1 receptor—and to a lesser extent an anticholinergic—specifically an antagonist of the muscarinic acetylcholine receptors M1 through M5. It is a first-generation antihistamine and crosses the blood–brain barrier into the brain, thereby producing centrally mediated sedative and hypnotic effects.

Doxylamine was first described in 1948 or 1949.[7] Several of the first-generation antihistamines, including doxylamine, are the most widely used sleep medications in the world.[8] Doxylamine is also a potent anticholinergic, which means it also works as a deliriant at much higher than recommended doses as a result.[9] Its sedative and deliriant effects have led to some cases of recreational use.

Medical uses

Doxylamine is an antihistamine used to treat sneezing, runny nose, watery eyes, hives, skin rash, itching, and other cold or allergy symptoms. It is also used as a short-term treatment for insomnia.[10]

Insomnia

The first-generation sedating antihistamines diphenhydramine, doxepin, doxylamine, and pyrilamine are the most widely used medications in the world for preventing and treating insomnia.[8] As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia.[11] As of 2008 and 2017, over-the-counter antihistamines were not recommended by the American Academy of Sleep Medicine for treatment of chronic insomnia "due to the relative lack of efficacy and safety data".[12][13] Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed.[12][13] A 2015 systematic review of over-the-counter sleep aids including doxylamine found little evidence to inform the use of doxylamine for treatment of insomnia.[4]

A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that doxylamine had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.47 (95% CI 0.06 to 0.89).[14] The certainty of evidence was rated as moderate.[14] No data were available for doxylamine in terms of longer-term treatment (3 months).[14] For comparison, the other sedating medicines assessed, doxepin and trimipramine (both of which are tricyclic antidepressants) had effect sizes (SMD) at 4 weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.55 (95% CI –0.11 to 1.21) (very low certainty evidence), respectively.[14]

Doses of doxylamine that have been used for sleep range from 5 to 50 mg, with 25 mg being the typical dose.[15][16][17][18]

Morning sickness

Doxylamine is used in the combination drug pyridoxine/doxylamine to treat morning sickness (nausea and vomiting of pregnancy).[19][20][21] It is the only medication approved by the United States Food and Drug Administration for the treatment of morning sickness.[19][20]

Available forms

Doxylamine is used medically as doxylamine succinate, the succinate salt of doxylamine, and is available both alone (brand names Decapryn, Doxy-Sleep-Aid, Unisom) and in combination with pyridoxine (a form of vitamin B6) (brand names Bendectin, Bonjesta, Diclegis).[22] Doxylamine is available alone as immediate-release oral tablets containing 25 mg doxylamine succinate.[22] Oral tablets containing 12.5 mg doxylamine succinate as well as oral capsules containing 25 mg doxylamine succinate were also previously available but were discontinued.[22] The combination of doxylamine and pyridoxine is available in the form of extended- and delayed-release oral tablets containing 10 to 20 mg doxylamine succinate and 10 to 20 mg pyridoxine hydrochloride.[22] Doxylamine alone is available over-the-counter, whereas doxylamine in combination with pyridoxine is a prescription-only medication.[22] Doxylamine is also available in over-the-counter nighttime cold medicine products such as NyQuil Cold & Flu (contains acetaminophen, doxylamine succinate 6.25 to 12.5 mg, and dextromethorphan hydrobromide), where it serves as the sedating component.[23][24]

Contraindications

The fetal safety rating of doxylamine is "A" (no evidence of risk).[25]

Side effects

Side effects of doxylamine include dizziness, drowsiness, and dry mouth, among others.[4] Doxylamine is a potent anticholinergic and has a side-effect profile common to such drugs, including blurred vision, dry mouth, constipation, muscle incoordination, urinary retention, mental confusion, and delirium.[18][6]

Because of its relatively long elimination half-life (10–12 hours), doxylamine is associated with next-day effects including sedation, drowsiness, grogginess, dry mouth, and tiredness when used as a hypnotic.[26][18] This may be described as a "hangover effect".[18] The shorter elimination half-life of diphenhydramine (4–8 hours) compared to doxylamine may give it an advantage over doxylamine as a sleep aid in this regard.[27]

Antihistamines like doxylamine are sedating initially but tolerance occurs with repeated use and can result in rebound insomnia upon discontinuation.[6][28]

Occasional case reports of coma and rhabdomyolysis have been reported with doxylamine.[2] This is in contrast to diphenhydramine.[2]

Studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse.[29] The carcinogenicity of the drug in humans is not well-studied, and the International Agency for Research on Cancer lists the drug as "not classifiable as to its carcinogenicity to humans".[30]

Continuous and/or cumulative use of anticholinergic medications, including first-generation antihistamines, is associated with a higher risk of cognitive decline and dementia in older people.[31][32]

Overdose

Doxylamine is generally safe for administration to healthy adults. Doses of doxylamine of up to 1,600 mg/day for 6 months have been given to adults with schizophrenia, with little toxicity encountered.[33] The median lethal dose (-1">50) is estimated to be 50–500 mg/kg in humans.[34] Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death.[35] Fatalities have been reported from doxylamine overdose. These have been characterized by coma, tonic-clonic (or grand mal) seizures and cardiopulmonary arrest. Children appear to be at a high risk for cardiopulmonary arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000 mg doxylamine succinate.[5] Rarely, an overdose results in rhabdomyolysis and acute kidney injury.[36]

Pharmacology

Pharmacodynamics

Site Ki (nM) Species Ref
NET >10,000 Human [37]
DAT >10,000 Human [37]
5-HT2A >10,000 Human [37]
5-HT2C >10,000 Human [37]
α1B >10,000 Human [37]
α2A >10,000 Human [37]
α2B >10,000 Human [37]
α2C >10,000 Human [37]
H1 42 Human [37]
H2 ND ND ND
H3 >10,000 Human [37]
H4 ND ND ND
M1 490 Human [37]
M2 2,100 Human [37]
M3 650 Human [37]
M4 380 Human [37]
M5 180 Human [37]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H1 receptor.[38][37] This action is responsible for its antihistamine and sedative properties.[38][37] To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors,[38][37] an action responsible for its anticholinergic and (at high doses) deliriant effects.[38][37]

Pharmacokinetics

The bioavailability of doxylamine is 24.7% for oral administration and 70.8% for intranasal administration.[1] The Tmax of doxylamine is 1.5 to 2.5 hours.[2] Its elimination half-life is 10 to 12 hours (range 7 to 15 hours).[2][3][4] Doxylamine is metabolized in the liver primarily by the cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP2C9.[2][39] The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide.[40] Doxylamine is eliminated 60% in the urine and 40% in feces.[5]

Doxylamine concentrations after a single 25 mg oral dose of doxylamine in healthy volunteers. X-axis represents the time in hours after initial dose.[3]

Chemistry

Doxylamine is a member of the ethanolamine class of antihistamines.[8] Other antihistamines from this group include bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, orphenadrine, and phenyltoloxamine.[8][41]

History

Doxylamine is a first-generation antihistamine and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949.[42][7][43] It has been the antihistamine component of NyQuil since 1966.[42]

Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), and dicyclomine (an anticholinergic antispasmodic agent), was marketed for treatment of morning sickness in 1956.[44] This product was reformulated in 1976 to remove dicyclomine.[44] The reformulated product was voluntarily discontinued by the manufacturer in the United States in 1983 due to concerns about an alleged association with congenital limb defects.[44] However, these concerns have not been supported by studies.[19][20] In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis.[19][20] The combination was not removed from the market in Canada, where it had been marketed since 1979.[19][20]

Society and culture

Formulations

Doxylamine is primarily used as the succinic acid salt, doxylamine succinate.

  • It is the sedating ingredient of NyQuil (generally in combination with dextromethorphan and acetaminophen).
  • In Commonwealth countries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared with paracetamol (acetaminophen) and codeine under the brand name Dolased, Propain Plus, Syndol, or Mersyndol, as treatment for tension headache and other types of pain.
  • Doxylamine succinate is used in general over-the-counter sleep-aids branded as Somnil (South Africa), Dozile, Donormyl, Lidène (France, Russian Federation), Dormidina (Spain, Portugal), Restavit, Unisom-2, Sominar (Thailand), Sleep Aid (generic, Australia) and Dorminox (Poland).
  • In the United States:
    • Doxylamine succinate is the active ingredient in many over-the-counter sleep-aids branded under various names.
    • Doxylamine succinate and pyridoxine (Vitamin B6) are the ingredients of Diclegis, approved by the FDA in April 2013 becoming the only drug approved for morning sickness[45] with a class A safety rating for pregnancy (no evidence of risk).
  • In Canada :
    • Doxylamine succinate and pyridoxine (vitamin B6) are the ingredients of Diclectin, which is used to prevent morning sickness.
    • It is also available in combination with vitamin B6 and folic acid under the brand name Evanorm (marketed by Ion Healthcare).
  • In India
    • Doxylamine preparations are available typically in combination with pyridoxine that may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.

References

  1. ↑ 1.0 1.1 1.2 "Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats". Biopharmaceutics & Drug Disposition 23 (6): 239–244. September 2002. doi:10.1002/bdd.314. PMID 12214324. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Principles and Practice of Sleep Medicine E-Book. Elsevier Health Sciences. 1 November 2010. p. 925. ISBN 978-1-4377-2773-9. https://books.google.com/books?id=3B52V4PnrVkC&pg=PA925. 
  3. ↑ 3.0 3.1 3.2 "A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment". Drugs in R&D 18 (2): 129–136. June 2018. doi:10.1007/s40268-018-0232-1. PMID 29671128. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety". The Primary Care Companion for CNS Disorders 17 (6). 2015. doi:10.4088/PCC.15r01798. PMID 27057416. 
  5. ↑ 5.0 5.1 5.2 "New Zealand Datasheet: Doxylamine Succinate". Medsafe, New Zealand Medicines and Medical Devices Safety Authority. 16 July 2008. http://www.medsafe.govt.nz/profs/datasheet/d/Dozilecap.pd. 
  6. ↑ 6.0 6.1 6.2 "The evolution and development of insomnia pharmacotherapies". Journal of Clinical Sleep Medicine 3 (5 Suppl): S11–S15. August 2007. doi:10.5664/jcsm.26930. PMID 17824496. 
  7. ↑ 7.0 7.1 Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 546. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA546. 
  8. ↑ 8.0 8.1 8.2 8.3 "Histamine and H1-antihistamines: celebrating a century of progress". The Journal of Allergy and Clinical Immunology 128 (6): 1139–1150.e4. December 2011. doi:10.1016/j.jaci.2011.09.005. PMID 22035879. 
  9. ↑ "Doxylamine - PsychonautWiki". https://psychonautwiki.org/wiki/Doxylamine. 
  10. ↑ "Doxylamine: MedlinePlus Drug Information". https://medlineplus.gov/druginfo/meds/a682537.html. 
  11. ↑ "Treatment of primary insomnia". The Journal of the American Board of Family Practice 17 (3): 212–219. 2004. doi:10.3122/jabfm.17.3.212. PMID 15226287. 
  12. ↑ 12.0 12.1 "Clinical guideline for the evaluation and management of chronic insomnia in adults". Journal of Clinical Sleep Medicine 4 (5): 487–504. October 2008. doi:10.5664/jcsm.27286. PMID 18853708. 
  13. ↑ 13.0 13.1 "Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline". Journal of Clinical Sleep Medicine 13 (2): 307–349. February 2017. doi:10.5664/jcsm.6470. PMID 27998379. 
  14. ↑ 14.0 14.1 14.2 14.3 "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis". Lancet 400 (10347): 170–184. July 2022. doi:10.1016/S0140-6736(22)00878-9. PMID 35843245. 
  15. ↑ Psychotropic Drug Handbook. Lippincott Williams & Wilkins. 2007. ISBN 9780781762731. https://books.google.com/books?id=h7lva61Muq4C&pg=PA377. 
  16. ↑ "[The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin]" (in French). L'Encephale 46 (1): 80–82. February 2020. doi:10.1016/j.encep.2019.01.006. PMID 30879783. 
  17. ↑ "Pharmacological Treatment of Insomnia". P & T 40 (11): 759–771. November 2015. PMID 26609210. 
  18. ↑ 18.0 18.1 18.2 18.3 "The therapeutic versatility of antihistamines: A comprehensive review". The Nurse Practitioner 45 (2): 8–21. February 2020. doi:10.1097/01.NPR.0000651112.76528.ed. PMID 31913218. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 "Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview". International Journal of Women's Health 6: 401–409. 2014. doi:10.2147/IJWH.S46653. PMID 24748822. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 "The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin ®) for the treatment of nausea and vomiting of pregnancy". Paediatric Drugs 16 (3): 199–211. June 2014. doi:10.1007/s40272-014-0065-5. PMID 24574047. 
  21. ↑ "Doxylamine succinate/pyridoxine hydrochloride". Hospital Pharmacy 48 (9): 762–766. October 2013. doi:10.1310/hpj4809-762. PMID 24421551. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 "Drugs@FDA: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. 
  23. ↑ "VICKS NYQUIL COLD AND FLU - acetaminophen, dextromethorphan hydrobromide, and doxylamine succinate capsule, liquid filled". DailyMed. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=620bc3dc-099b-40bd-be22-e4c3f9c8e09d. 
  24. ↑ "Nyquil Cold and Flu: Basics, Side Effects & Reviews". https://www.goodrx.com/nyquil/what-is. 
  25. ↑ Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Obstetric Medicine. 2. Lippincott Williams & Wilkins. 2008. pp. 89. doi:10.1258/om.2009.090002. ISBN 978-0-7817-7876-3. https://books.google.com/books?id=YOEV2w3XTxsC. 
  26. ↑ Review of Sleep Medicine E-Book. Elsevier Health Sciences. 2017. p. 394. ISBN 978-0-323-47349-1. https://books.google.com/books?id=hpwqDwAAQBAJ&pg=PA394. 
  27. ↑ Community Pharmacy ANZ – eBook: Symptoms, Diagnosis and Treatment. Elsevier Health Sciences. 11 September 2015. p. 99. ISBN 978-0-7295-8345-9. https://books.google.com/books?id=NbjVCgAAQBAJ&pg=PA99. 
  28. ↑ "Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines". CNS Spectrums 13 (12): 1027–1038. December 2008. doi:10.1017/s1092852900017089. PMID 19179941. 
  29. ↑ Doxylamine succinate (CAS 562-10-7) . berkeley.edu.
  30. ↑ DOXYLAMINE SUCCINATE. International Agency for Research on Cancer (IARC) – Summaries & Evaluations.
  31. ↑ "Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study". JAMA Internal Medicine 175 (3): 401–407. March 2015. doi:10.1001/jamainternmed.2014.7663. PMID 25621434. 
  32. ↑ "Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study". Archives of Internal Medicine 169 (14): 1317–1324. July 2009. doi:10.1001/archinternmed.2009.229. PMID 19636034. 
  33. ↑ Federal Register, Volume 43, Issues 114-121. Office of the Federal Register, National Archives and Records Service, General Services Administration. 1978. p. 25584. OCLC 1768512. https://books.google.com/books?id=NTG_12_vTEEC&pg=PA25584. 
  34. ↑ "DOXYLAMINE SUCCINATE". http://hazard.com/msds/mf/baker/baker/files/d8882.htm. 
  35. ↑ "Doxylamine toxicity: seizure, rhabdomyolysis and false positive urine drug screen for methadone". BMJ Case Reports 2009 (90): 845. 17 March 2009. doi:10.1136/bcr.09.2008.0879. PMID 21686586. 
  36. ↑ "Doxylamine overdose as a potential cause of rhabdomyolysis". The American Journal of the Medical Sciences 322 (1): 48–49. July 2001. doi:10.1097/00000441-200107000-00009. PMID 11465247. 
  37. ↑ 37.00 37.01 37.02 37.03 37.04 37.05 37.06 37.07 37.08 37.09 37.10 37.11 37.12 37.13 37.14 37.15 37.16 37.17 37.18 Cite error: Invalid <ref> tag; no text was provided for refs named pmid23357028
  38. ↑ 38.0 38.1 38.2 38.3 "Histamine-1 receptor antagonism for treatment of insomnia". Journal of the American Pharmacists Association 52 (6): e210–e219. 2012. doi:10.1331/JAPhA.2012.12051. PMID 23229983. 
  39. ↑ "A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice". Sleep Medicine Reviews 13 (4): 265–274. August 2009. doi:10.1016/j.smrv.2008.08.001. PMID 19153052. 
  40. ↑ "Mass spectral characterization of doxylamine and its rhesus monkey urinary metabolites". Biomedical Mass Spectrometry 12 (4): 151–158. April 1985. doi:10.1002/bms.1200120403. PMID 2861861. https://zenodo.org/record/1229133. 
  41. ↑ "Efficacy and safety of H1-antihistamines: an update". Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 11 (3): 230–237. 2012. doi:10.2174/1871523011202030230. PMID 23173575. 
  42. ↑ 42.0 42.1 Frontiers in Clinical Drug Research - Anti-Allergy Agents, Volume 3. Bentham Science Publishers. 11 July 2018. p. 30. ISBN 978-1-68108-337-7. OCLC 1048922805. https://books.google.com/books?id=EIJoDwAAQBAJ&pg=PA30. 
  43. ↑ "Pyridyl-substituted alkamine ethers as antihistaminic agents". Journal of the American Chemical Society 71 (3): 887–890. March 1949. doi:10.1021/ja01171a034. PMID 18113525. 
  44. ↑ 44.0 44.1 44.2 Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk (9 ed.). Lippincott Williams & Wilkins. 28 March 2012. p. 453. ISBN 978-1-4511-5359-0. OCLC 1232803849. https://books.google.com/books?id=ScPvM03B3lUC&pg=PA453. 
  45. ↑ "FDA approval of doxylamine-pyridoxine therapy for use in pregnancy". The New England Journal of Medicine 370 (12): 1081–1083. March 2014. doi:10.1056/NEJMp1316042. PMID 24645939. 



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